Actions of danazol in vivo on cytochrome P-450 and steroidogenic enzymes in rat testis and liver microsomal preparations.
The mechanism of action of danazol has not been established and the drug may act at multiple loci. Effects suggesting inhibition of pituitary gonadotropin release have been described while some in vitro studies have demonstrated competitive inhibition of steroidogenic enzymes. In addition, destruction of cytochrome P-450 by the acetylenic moiety of danazol is a possible mechanism. Following 14 days of danazol treatment (10 mg/kg/day), the specific content of rat testis microsomal cytochrome P-450 and the serum testosterone were decreased, in spite of no significant change in serum luteinizing hormone. Furthermore, simultaneous administration of human chorionic gonadotropin with danazol still resulted in a decrease in cytochrome. The activities of two testicular microsomal steroid-converting enzymes (17 alpha-hydroxylase and 17,20-lyase) were not altered when based on cytochrome P-450 content but were markedly depressed when based on microsomal protein. In liver, danazol showed a similar but less marked dimunition of the cytochrome. Surprisingly, steroid 17 alpha-hydroxylase activity in liver was significantly increased while other cytochrome P-450 dependent enzyme activities were not altered.
D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003613:Danazol / Q000494:pharmacology*; D005640:Follicle Stimulating Hormone / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008190:Lyases / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011245:Pregnadienes / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000648:ultrastructure*; D013739:Testosterone / Q000097:blood
D006063:Chorionic Gonadotropin; D011245:Pregnadienes; D011506:Proteins; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000815:Aniline Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D009245:NADH Dehydrogenase; D008190:Lyases; D003613:Danazol